CA2764603A1 - Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid by poor-solvent addition method - Google Patents
Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid by poor-solvent addition method Download PDFInfo
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- CA2764603A1 CA2764603A1 CA2764603A CA2764603A CA2764603A1 CA 2764603 A1 CA2764603 A1 CA 2764603A1 CA 2764603 A CA2764603 A CA 2764603A CA 2764603 A CA2764603 A CA 2764603A CA 2764603 A1 CA2764603 A1 CA 2764603A1
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- isobutyloxyphenyl
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- thiazolecarboxylic acid
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- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 239000002904 solvent Substances 0.000 title claims abstract description 55
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 25
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 10
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 10
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000011109 contamination Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 description 2
- 150000007979 thiazole derivatives Chemical class 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a process for producing A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from the group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
Description
Process for Producing Crystals of Polymorphic
2-(3-Cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic Acid by Poor-Solvent Addition Method Technical Field The, present invention relates to a process for producing A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid. The compound has an activity of regulating biosynthesis of uric acid in vivo and can be used, for example, as a therapeutic agent for hyperuricemia.
Background Art In producing drugs, control of crystal polymorphs of chemical substances, the bulk powder, is recognized as an important matter because a difference in the polymorphs has a great influence on the properties as a drug such as a pharmaceutical function, bioavailability, stability, and the like. This is as stated in the ICH
(International Conference on Harmonisation) Q6A guideline, "Specifications: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances."
With regard to the polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, PTL 1 discloses presence of 5 kinds of polymorphs, including A-form crystals, B-form crystals, C-form crystals, D-form crystals, and G-form crystals, as well as an amorphous material. Also disclosed are methods for producing the same. The methods for producing the polymorphs disclosed herein are for producing each of the polymorphs, comprising:
I
adding a predetermined amount of a mixed solvent of methanol or 2-propanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid;
dissolving the mixture by stirring under heat; setting the methanol/water composition and the like and temperature to predetermined values by addition of water and cooling; and thereafter collecting crystals by filtration and drying the same.
However, influences of the initial concentration referred to in PTL 1 are only on the chemical purity and the amounts of the recovered product, and effects on the polymorphs obtained are not described. In addition, in the case of crystallization from a mixed solvent of 2-propanol and water, it is only described that the G-form crystals are obtained.
Furthermore, at International Symposium on Industrial Crystallization (September 21 -25, 1998, Tianjin, China), M. Kitamura, M. Hanada, K. Nakamura, and others have shown in "Crystallization and transformation behavior of the polymorphs of thiazole-derivative"
(see NPL 1) that, under the condition of a methanol/water composition and temperature where only the A-form crystals were thought to be obtained, the G-form crystals or a mixture of the A-form crystals and the G-form crystals were obtained in some cases at the time of crystallization, when water addition time was drastically changed substantially. In addition, they have also shown that, by subsequently changing the temperature of the crystallization liquid and by keeping the liquid in a state of agitation, the crystals were transformed to the D-form crystals.
When industrially useful A-form crystals are to be produced, these heretofore known methods are not pronounced to be completely free from contamination by the G-form crystals. Moreover, in order to avoid contamination by the G-form crystals, the water addition time is restricted and, thus, there is also a problem that a long time is required for industrial production.
Meanwhile, PTL 2 discloses a method for producing the polymorphs by addition of water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid dissolved in methanol or a mixed solvent of methanol/water, wherein the initial concentrations and water addition time are varied to obtain the A-form crystals, the G-form crystals, or a mixture of A-form and the G-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
However, crystallization using these heretofore known mixed solvent systems, for example crystallization using a mixed solvent system of methanol/water with a ratio of 7/3 provides crystals of a form different from the A-form crystals or a mixture of A-form crystals and crystals of a form different therefrom. Thus, it has not been possible to obtain the A-form crystals stably.
Citation List Patent Literature PTL 1: International Publication No. W099/65885 PTL 2: Japanese Patent Laid-Open Publication No. 2003-261548 [Non Patent Literature]
NPL 1: M. Kitamura and K. Nakamura, "Crystallization and transformation behavior of the polymorphs of thiazole-derivative," Abstract of Autumn Meeting of the Society of Chemical Engineers, Japan, Vol. 33, p. 653 (2000. 08. 12)
Background Art In producing drugs, control of crystal polymorphs of chemical substances, the bulk powder, is recognized as an important matter because a difference in the polymorphs has a great influence on the properties as a drug such as a pharmaceutical function, bioavailability, stability, and the like. This is as stated in the ICH
(International Conference on Harmonisation) Q6A guideline, "Specifications: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances."
With regard to the polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, PTL 1 discloses presence of 5 kinds of polymorphs, including A-form crystals, B-form crystals, C-form crystals, D-form crystals, and G-form crystals, as well as an amorphous material. Also disclosed are methods for producing the same. The methods for producing the polymorphs disclosed herein are for producing each of the polymorphs, comprising:
I
adding a predetermined amount of a mixed solvent of methanol or 2-propanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid;
dissolving the mixture by stirring under heat; setting the methanol/water composition and the like and temperature to predetermined values by addition of water and cooling; and thereafter collecting crystals by filtration and drying the same.
However, influences of the initial concentration referred to in PTL 1 are only on the chemical purity and the amounts of the recovered product, and effects on the polymorphs obtained are not described. In addition, in the case of crystallization from a mixed solvent of 2-propanol and water, it is only described that the G-form crystals are obtained.
Furthermore, at International Symposium on Industrial Crystallization (September 21 -25, 1998, Tianjin, China), M. Kitamura, M. Hanada, K. Nakamura, and others have shown in "Crystallization and transformation behavior of the polymorphs of thiazole-derivative"
(see NPL 1) that, under the condition of a methanol/water composition and temperature where only the A-form crystals were thought to be obtained, the G-form crystals or a mixture of the A-form crystals and the G-form crystals were obtained in some cases at the time of crystallization, when water addition time was drastically changed substantially. In addition, they have also shown that, by subsequently changing the temperature of the crystallization liquid and by keeping the liquid in a state of agitation, the crystals were transformed to the D-form crystals.
When industrially useful A-form crystals are to be produced, these heretofore known methods are not pronounced to be completely free from contamination by the G-form crystals. Moreover, in order to avoid contamination by the G-form crystals, the water addition time is restricted and, thus, there is also a problem that a long time is required for industrial production.
Meanwhile, PTL 2 discloses a method for producing the polymorphs by addition of water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid dissolved in methanol or a mixed solvent of methanol/water, wherein the initial concentrations and water addition time are varied to obtain the A-form crystals, the G-form crystals, or a mixture of A-form and the G-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
However, crystallization using these heretofore known mixed solvent systems, for example crystallization using a mixed solvent system of methanol/water with a ratio of 7/3 provides crystals of a form different from the A-form crystals or a mixture of A-form crystals and crystals of a form different therefrom. Thus, it has not been possible to obtain the A-form crystals stably.
Citation List Patent Literature PTL 1: International Publication No. W099/65885 PTL 2: Japanese Patent Laid-Open Publication No. 2003-261548 [Non Patent Literature]
NPL 1: M. Kitamura and K. Nakamura, "Crystallization and transformation behavior of the polymorphs of thiazole-derivative," Abstract of Autumn Meeting of the Society of Chemical Engineers, Japan, Vol. 33, p. 653 (2000. 08. 12)
3 Summary of Invention Technical Problem An object of the present invention is to selectively and stably obtain the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid under conditions suitable for commercial production.
Solution to Problem The present invention is a process for producing A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from the group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
That is, the present invention is based on the finding that the A-form crystals can be obtained stably by using a lower alcohol solvent except methanol or acetone as the good solvent and by using a hydrocarbon solvent as the poor solvent.
Here, the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid refer to a polymorph which shows an X-ray powder diffraction pattern having characteristic peaks at, when represented in terms of a reflection angle 20, about 6.62 , 7.18 , 12.800, 13.26 , 16.48 , 19.58 , 21.92 , 22.68 , 25.84 , 26.70',29.161, and 36.700. One example of such X-ray powder diffraction patterns is shown in Figure 1 (the X-ray diffractometer used is different from the one used in PTL 1). Alternatively, in an infrared spectroscopic analysis, the A-form crystals may be expressed as a polymorph having a
Solution to Problem The present invention is a process for producing A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from the group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
That is, the present invention is based on the finding that the A-form crystals can be obtained stably by using a lower alcohol solvent except methanol or acetone as the good solvent and by using a hydrocarbon solvent as the poor solvent.
Here, the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid refer to a polymorph which shows an X-ray powder diffraction pattern having characteristic peaks at, when represented in terms of a reflection angle 20, about 6.62 , 7.18 , 12.800, 13.26 , 16.48 , 19.58 , 21.92 , 22.68 , 25.84 , 26.70',29.161, and 36.700. One example of such X-ray powder diffraction patterns is shown in Figure 1 (the X-ray diffractometer used is different from the one used in PTL 1). Alternatively, in an infrared spectroscopic analysis, the A-form crystals may be expressed as a polymorph having a
4 characteristic absorption at around 1678 cm 1, which is distinguishable from other polymorphs (see PTL 1).
Advantageous Effects of Invention In contrast to crystallization using water as the poor solvent, the conventional technology, where crystals are obtained under certain conditions as solvates, hydrates, or a mixture thereof, the production process of the present invention has an effect that the A-form crystals can be obtained selectively and stably by using a hydrocarbon solvent as the poor solvent.
That is, according to the production process of the present invention, the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid can be produced under conditions suitable for commercial production, while lowering the possibility of intermingling of other crystal forms.
Brief Description of Drawings Figure 1 shows an X-ray powder diffraction pattern and a peak list of the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
Description of Embodiments The present invention is a process for producing the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from a group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
When a plurality of solvents are used as the good solvent, they may be mixed in advance and used as a mixed solvent or each solvent may be added successively.
Here, the ratio of solute/solvent when dissolving the solute in a good solvent is as follows: when the solvent is ethanol, I -propanol, or 2-propanol, the ratio is preferably in a range from 0.05 to 0.5 g/mL and, further, more preferably in a range from 0.08 to 0.25 g/mL; and when the solvent is acetone, the ratio is preferably in a range from 0.05 to 0.l g/mL and, further, more preferably in a range from 0.08 to 0.09 g/mL.
Conditions for a cooling operation in the production process of the present invention are not particularly limited as long as an effect as crystallization is manifested.
As such conditions, there may be considered temperature before and after cooling, a period of time for cooling (further, a time curve of the liquid temperature), means for cooling such as cooling devices and the like, presence or absence of stirring, stirrers and rate of stirring when stirring is used, vessels to be used, and the like.
Regarding these, one skilled in the art may find suitable conditions for given prerequisites by referring to Examples, mentioned later while considering necessary amounts of crystals, period of time, costs, available equipment, and the like.
If necessary, the conditions may be determined by preliminary experiments. In addition, the temperature before cooling must be determined by considering the boiling point of the solvent used. Further, if the temperature after cooling is too low, there may be formed solvates depending on the solvent used and, therefore, it is desirable to confirm the conditions beforehand. Further, when acetone is used as the good solvent, care must be taken because other crystal forms may get intermingled if the solution is not cooled rapidly. From this viewpoint, also, it is desirable that the conditions are confirmed in advance.
One example of the period of time for cooling is ca. 15 minutes=(except when the solvent is acetone).
As a hydrocarbon solvent used as the poor solvent, preferable are heptane and/or hexane and, especially preferable is heptane.
Furthermore, the amount of such poor solvent is such that the ratio of solute/(poor solvent added) is preferably in a range from 0.05 to 0.4 g/mL and, further, more preferably in a range from 0.06 to 0.4 g/mL.
In the production process of the present invention, the order of the step of cooling a solution of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and the step of adding a poor solvent to the solution is not particularly limited.
Either step may be carried out first, or whole or part of these steps may be carried out concurrently.
In the conventional production process where water is used as a solvent, there is a possibility that the crystals may be transformed to solvates depending on the method of drying after crystallization and the like. However, in the production method of the present invention, water is not used as the solvent and, therefore, there is no possibility of transformation of the crystals to the hydrates, enabling use of a variety of methods as the drying method after crystallization.
In the production process of the present invention where a hydrocarbon solvent is used as the poor solvent, the hydrocarbon solvent does not form solvates with 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, thus providing a wide stable region in crystallization conditions for obtaining the desired A-form crystals.
Further, in the production process of the present invention, when 1-propanol or 2-propanol is used as the good solvent, no solvates with 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid are formed, thus providing a wide stable region in crystallization conditions for obtaining the desired A-form crystals. Based on these findings, when a combination of 1-propanol or 2-propanol and a hydrocarbon solvent, especially heptane, is used as the solvent, the A-form crystals can be obtained stably over wider solvent ratios and a wider range of temperature than the conventional art.
In addition, because the solvents used in the present production process are only organic solvents without using water, the present process has superiority also in that it provides higher purification efficiency for hydrophobic impurities.
Examples Example 1 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 57 mL of ethanol and the mixture was heated to complete dissolution.
While maintaining the solution at 40 C or higher, 133 mL of heptane was added thereto. This solution was cooled to 40 C and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 2 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 115 mL of 2-propanol and the mixture was heated to complete dissolution.
While maintaining the solution at room temperature or higher, 67 mL of heptane was added thereto. This solution was cooled to room temperature and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 3 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 40 mL of 1-propanol and the mixture was heated to complete dissolution.
While maintaining the solution at room temperature or higher, 80 mL of heptane was added thereto. This solution was cooled to 0 C and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 4 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 115 mL of acetone and the mixture was heated to complete dissolution.
The solution was cooled rapidly to 15 C using an ice bath and 67 mL of heptane was added thereto. Crystals which separated were collected by filtration, followed by drying.
The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Industrial Applicability The A-form crystals of 2-(3-cyan-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid obtained by the production process of the present invention can be used as a drug.
Advantageous Effects of Invention In contrast to crystallization using water as the poor solvent, the conventional technology, where crystals are obtained under certain conditions as solvates, hydrates, or a mixture thereof, the production process of the present invention has an effect that the A-form crystals can be obtained selectively and stably by using a hydrocarbon solvent as the poor solvent.
That is, according to the production process of the present invention, the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid can be produced under conditions suitable for commercial production, while lowering the possibility of intermingling of other crystal forms.
Brief Description of Drawings Figure 1 shows an X-ray powder diffraction pattern and a peak list of the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
Description of Embodiments The present invention is a process for producing the A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from a group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
When a plurality of solvents are used as the good solvent, they may be mixed in advance and used as a mixed solvent or each solvent may be added successively.
Here, the ratio of solute/solvent when dissolving the solute in a good solvent is as follows: when the solvent is ethanol, I -propanol, or 2-propanol, the ratio is preferably in a range from 0.05 to 0.5 g/mL and, further, more preferably in a range from 0.08 to 0.25 g/mL; and when the solvent is acetone, the ratio is preferably in a range from 0.05 to 0.l g/mL and, further, more preferably in a range from 0.08 to 0.09 g/mL.
Conditions for a cooling operation in the production process of the present invention are not particularly limited as long as an effect as crystallization is manifested.
As such conditions, there may be considered temperature before and after cooling, a period of time for cooling (further, a time curve of the liquid temperature), means for cooling such as cooling devices and the like, presence or absence of stirring, stirrers and rate of stirring when stirring is used, vessels to be used, and the like.
Regarding these, one skilled in the art may find suitable conditions for given prerequisites by referring to Examples, mentioned later while considering necessary amounts of crystals, period of time, costs, available equipment, and the like.
If necessary, the conditions may be determined by preliminary experiments. In addition, the temperature before cooling must be determined by considering the boiling point of the solvent used. Further, if the temperature after cooling is too low, there may be formed solvates depending on the solvent used and, therefore, it is desirable to confirm the conditions beforehand. Further, when acetone is used as the good solvent, care must be taken because other crystal forms may get intermingled if the solution is not cooled rapidly. From this viewpoint, also, it is desirable that the conditions are confirmed in advance.
One example of the period of time for cooling is ca. 15 minutes=(except when the solvent is acetone).
As a hydrocarbon solvent used as the poor solvent, preferable are heptane and/or hexane and, especially preferable is heptane.
Furthermore, the amount of such poor solvent is such that the ratio of solute/(poor solvent added) is preferably in a range from 0.05 to 0.4 g/mL and, further, more preferably in a range from 0.06 to 0.4 g/mL.
In the production process of the present invention, the order of the step of cooling a solution of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and the step of adding a poor solvent to the solution is not particularly limited.
Either step may be carried out first, or whole or part of these steps may be carried out concurrently.
In the conventional production process where water is used as a solvent, there is a possibility that the crystals may be transformed to solvates depending on the method of drying after crystallization and the like. However, in the production method of the present invention, water is not used as the solvent and, therefore, there is no possibility of transformation of the crystals to the hydrates, enabling use of a variety of methods as the drying method after crystallization.
In the production process of the present invention where a hydrocarbon solvent is used as the poor solvent, the hydrocarbon solvent does not form solvates with 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, thus providing a wide stable region in crystallization conditions for obtaining the desired A-form crystals.
Further, in the production process of the present invention, when 1-propanol or 2-propanol is used as the good solvent, no solvates with 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid are formed, thus providing a wide stable region in crystallization conditions for obtaining the desired A-form crystals. Based on these findings, when a combination of 1-propanol or 2-propanol and a hydrocarbon solvent, especially heptane, is used as the solvent, the A-form crystals can be obtained stably over wider solvent ratios and a wider range of temperature than the conventional art.
In addition, because the solvents used in the present production process are only organic solvents without using water, the present process has superiority also in that it provides higher purification efficiency for hydrophobic impurities.
Examples Example 1 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 57 mL of ethanol and the mixture was heated to complete dissolution.
While maintaining the solution at 40 C or higher, 133 mL of heptane was added thereto. This solution was cooled to 40 C and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 2 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 115 mL of 2-propanol and the mixture was heated to complete dissolution.
While maintaining the solution at room temperature or higher, 67 mL of heptane was added thereto. This solution was cooled to room temperature and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 3 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 40 mL of 1-propanol and the mixture was heated to complete dissolution.
While maintaining the solution at room temperature or higher, 80 mL of heptane was added thereto. This solution was cooled to 0 C and crystals which separated were collected by filtration, followed by drying. The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Example 4 To 10 g of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was added 115 mL of acetone and the mixture was heated to complete dissolution.
The solution was cooled rapidly to 15 C using an ice bath and 67 mL of heptane was added thereto. Crystals which separated were collected by filtration, followed by drying.
The crystals obtained were analyzed by X-ray powder diffraction and were found to be A-form crystals.
Industrial Applicability The A-form crystals of 2-(3-cyan-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid obtained by the production process of the present invention can be used as a drug.
Claims (4)
1. A process for producing A-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising: a step of dissolving by heating 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid in one or a plurality of solvents as a good solvent, selected from the group consisting of 1-propanol, 2-propanol, ethanol, and acetone; a step of cooling the solution; and a step of adding to the solution a hydrocarbon solvent as a poor solvent.
2. The production process according to claim 1, wherein the good solvent is one solvent selected from the group consisting of 1-propanol, 2-propanol, ethanol, and acetone.
3. The production process according to claim 1 or 2, wherein the poor solvent is heptane and/or hexane.
4. The production process according to claim 1 or 2, wherein the poor solvent is heptane.
Applications Claiming Priority (3)
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| JP2009166755 | 2009-07-15 | ||
| JP2009-166755 | 2009-07-15 | ||
| PCT/JP2010/062291 WO2011007895A1 (en) | 2009-07-15 | 2010-07-14 | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecaboxylic acid by poor-solvent addition method |
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| CA2764603A1 true CA2764603A1 (en) | 2011-01-20 |
| CA2764603C CA2764603C (en) | 2017-03-14 |
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| EP (1) | EP2455372B1 (en) |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267957A (en) * | 2011-08-24 | 2011-12-07 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
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| EP2502920A1 (en) | 2011-03-25 | 2012-09-26 | Sandoz Ag | Crystallization process of Febuxostat from A |
| CN103936688A (en) * | 2013-01-21 | 2014-07-23 | 上海华拓医药科技发展股份有限公司 | Preparation method of 2-(3-cyano-4-(2-methyl propoxy) phenyl)-4-methyl-5-thiazolecarboxylic acid crystal A |
| CN103588723B (en) * | 2013-09-10 | 2015-05-20 | 杭州华东医药集团新药研究院有限公司 | Preparation method for novel febuxostat crystal form A |
| CN103739568B (en) * | 2014-02-07 | 2015-09-16 | 浙江普洛康裕制药有限公司 | The preparation method of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid A crystal formation |
| RU2016148736A (en) * | 2014-05-13 | 2018-06-14 | Тейдзин Фарма Лимитед | NEW CRYSTALLINE POLYMORPHES OF PYRIDINE DERIVATIVE AND METHOD FOR PRODUCING THEM |
| KR20180013563A (en) * | 2016-07-29 | 2018-02-07 | 한미정밀화학주식회사 | Improved method for preparing high purity crystalline febuxostate |
| CN111499655B (en) * | 2019-01-31 | 2023-01-06 | 华东理工大学 | Three-liquid emulsion solvent diffusion method for preparing spherical crystal |
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| TR200000458T1 (en) * | 1998-06-19 | 2000-10-23 | Teijin Limited | 2- (3-cyano-4-isobutyloxyphenyl) -4-Methyl-5-thiazolecarboxylic acid and method for producing it. |
| JP2003261548A (en) | 2002-03-07 | 2003-09-19 | Teijin Ltd | Method of producing polymorphic crystal of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid |
| JPWO2006115137A1 (en) * | 2005-04-22 | 2008-12-18 | キッセイ薬品工業株式会社 | 2-Aminobenzimidazole derivatives and their pharmaceutical use |
| CN101139325B (en) * | 2006-09-07 | 2010-05-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof |
| CN101684107A (en) | 2008-09-26 | 2010-03-31 | 上海优拓医药科技有限公司 | New febuxostat crystal form and preparing method thereof |
| CN101684108B (en) | 2009-04-15 | 2012-01-11 | 天津市汉康医药生物技术有限公司 | 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and composition thereof |
| JP5215505B2 (en) * | 2009-06-10 | 2013-06-19 | テバ ファーマシューティカル インダストリーズ リミティド | Crystal form of febuxostat |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267957A (en) * | 2011-08-24 | 2011-12-07 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
| CN102267957B (en) * | 2011-08-24 | 2013-04-24 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
Also Published As
| Publication number | Publication date |
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| AU2010271717A8 (en) | 2012-03-08 |
| AU2010271717B2 (en) | 2014-11-27 |
| IL217509A (en) | 2016-04-21 |
| EP2455372A4 (en) | 2012-12-05 |
| TW201118076A (en) | 2011-06-01 |
| US20120108821A1 (en) | 2012-05-03 |
| EP2455372A1 (en) | 2012-05-23 |
| KR101645768B1 (en) | 2016-08-04 |
| IL217509A0 (en) | 2012-03-01 |
| RU2530895C2 (en) | 2014-10-20 |
| CA2764603C (en) | 2017-03-14 |
| RU2012105279A (en) | 2013-08-20 |
| TWI516480B (en) | 2016-01-11 |
| EP2455372B1 (en) | 2017-10-11 |
| KR20120036363A (en) | 2012-04-17 |
| CN102471295B (en) | 2014-07-16 |
| ES2647239T3 (en) | 2017-12-20 |
| JPWO2011007895A1 (en) | 2012-12-27 |
| WO2011007895A1 (en) | 2011-01-20 |
| CN102471295A (en) | 2012-05-23 |
| AU2010271717A1 (en) | 2011-01-20 |
| MX2011013946A (en) | 2012-01-25 |
| JP5654462B2 (en) | 2015-01-14 |
| BRPI1011671A2 (en) | 2016-03-22 |
| SG177673A1 (en) | 2012-02-28 |
| US8735596B2 (en) | 2014-05-27 |
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